Necrotising enterocolitis (NEC) is a devastating bowel disease, primarily affecting premature infants, with a poorly understood aetiology. Prior studies have found associations in different cases with an overabundance of particular elements of the faecal microbiota (in particular Enterobacteriaceae or Clostridium perfringens), but there has been no explanation for the different results found in different cohorts. Immunological studies have indicated that stimulation of the TLR4 receptor is involved in development of NEC, with TLR4 signalling being antagonised by the activated TLR9 receptor. We speculated that differential stimulation of these two components of the signalling pathway by different microbiota might explain the dichotomous findings of microbiota-centered NEC studies. Here we used shotgun metagenomic sequencing and qPCR to characterise the faecal microbiota community of infants prior to NEC onset and in a set of matched controls. Bayesian regression was used to segregate cases from control samples using both microbial and clinical data. We found that the infants suffering from NEC fell into two groups based on their microbiota; one with low levels of CpG DNA in bacterial genomes and the other with high abundances of organisms expressing LPS. The identification of these characteristic communities was reproduced using an external metagenomic validation dataset. We propose that these two patterns represent the stimulation of a common pathway at extremes; the LPS-enriched microbiome suggesting overstimulation of TLR4, whilst a microbial community with low levels of CpG DNA suggests reduction of the counterbalance to TLR4 overstimulation. The identified microbial community patterns support the concept of NEC resulting from TLR-mediated pathways. Identification of these signals suggests characteristics of the gastrointestinal microbial community to be avoided to prevent NEC. Potential pre- or pro-biotic treatments may be designed to optimise TLR signalling.

中文翻译：

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支持上皮 TLR 介导的坏死性小肠结肠炎通路的早产新生儿肠道微生物群落模式

坏死性小肠结肠炎 (NEC) 是一种毁灭性的肠道疾病，主要影响早产儿，其病因学知之甚少。先前的研究发现，在不同情况下，粪便微生物群的特定元素（特别是肠杆菌科或产气荚膜梭菌）过多与过量存在关联，但没有对不同队列中发现的不同结果做出解释。免疫学研究表明，TLR4 受体的刺激参与 NEC 的发展，TLR4 信号传导被激活的 TLR9 受体拮抗。我们推测，不同微生物群对信号通路的这两种成分的不同刺激可能解释了以微生物群为中心的 NEC 研究的二分法发现。在这里，我们使用鸟枪法宏基因组测序和 qPCR 来表征 NEC 发作前和一组匹配对照中的婴儿粪便微生物群落。贝叶斯回归用于使用微生物和临床数据将病例与对照样本分开。我们发现患有 NEC 的婴儿根据他们的微生物群分为两组；一种在细菌基因组中具有低水平的 CpG DNA，另一种具有高丰度的表达 LPS 的生物体。使用外部宏基因组验证数据集再现了这些特征群落的识别。我们认为这两种模式代表了极端情况下共同途径的刺激；富含 LPS 的微生物组表明过度刺激 TLR4，而具有低水平 CpG DNA 的微生物群落表明 TLR4 过度刺激的平衡减少。已确定的微生物群落模式支持由 TLR 介导的途径产生的 NEC 概念。对这些信号的鉴定表明，为预防 NEC，应避免胃肠道微生物群落的特征。可以设计潜在的益生菌或益生菌治疗以优化 TLR 信号传导。